Indications
  • KYPROLIS® (carfilzomib) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
  • KYPROLIS® is indicated as a single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
  • ... Read More 
NOW APPROVED
DKd: KYPROLIS®+Darzalex® (daratumumab)+dexamethasone
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Safety: Kd vs Vd study

Safety experience

Discontinuation due to adverse reactions and disease progression across treatment arms1,2

Discontinuation due to adverse reactions and disease progression
Kd vs Vd: Discontinuation due to adverse reactions and disease progression across treatment armsKd vs Vd: Discontinuation due to adverse reactions and disease progression across treatment arms

Safety experience with Kd 56 mg/m2 vs Vd1,2

  • Deaths due to adverse reactions within 30 days of the last dose of any therapy in the Kd arm occurred in 7% of patients compared with 5% of patients in the Vd arm1
  • The causes of death in patients in the 2 arms (Kd vs Vd) included (n, %): cardiac (4, 1% vs 5, 1%), infections (8, 2% vs 8, 2%), disease progression (7, 2% vs 4, 1%), pulmonary (3, 1% vs 2, < 1%), renal (1, < 1% vs 0, 0%), and other adverse reactions (9, 2% vs 2, < 1%)1
  • Dose reductions due to adverse reactions: 23% of patients in the Kd arm experienced dose reductions due to adverse reactions vs 48% in the Vd arm2

Safety profile

Additional safety and clinical considerations1,2

  • The overall incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm1
  • The frequency of Grade ≥ 3 cardiac failure events was observed in 5% of Kd patients2
  • Death due to cardiac issues occurred in 4 Kd patients vs 5 Vd patients (1% vs 1%)1
Select adverse reactions of interest2
Kd (n = 463) Vd (n = 456)
Preferred term All grades Grade ≥ 3 All grades Grade ≥ 3
Acute renal failure* 8% 4% 5% 3%
Cardiac failure 8% 5% 3% 2%
Ischemic heart disease 3% 2% 2% 2%
Peripheral neuropathy§ 19% 2% 52% 8%
Pulmonary hypertension** 1% 1% 0.2% 0.2%

In the Kd arm, the most common treatment-emergent adverse reactions were predominantly Grade 1/21

Most common adverse reactions (≥ 10% in the Kd treatment arm) occurring in months 1-6 of the Kd vs Vd study1
Kd (n = 463)
n (%)
Vd (n = 456)
n (%)
Adverse reaction by body system Any grade Grade ≥ 3 Any grade Grade ≥ 3
Blood and lymphatic system disorders
Anemia 161 (35%) 57 (12%) 112 (25%) 43 (9%)
Thrombocytopenia* 125 (27%) 45 (10%) 112 (25%) 64 (14%)
Gastrointestinal disorders
Diarrhea 117 (25%) 14 (3%) 149 (33%) 27 (6%)
Nausea 70 (15%) 4 (1%) 68 (15%) 3 (1%)
Constipation 60 (13%) 1 (0%) 113 (25%) 6 (1%)
Vomiting 45 (10%) 5 (1%) 33 (7%) 3 (1%)
General disorders and administration site conditions
Fatigue 116 (25%) 14 (3%) 126 (28%) 25 (6%)
Pyrexia 102 (22%) 9 (2%) 52 (11%) 3 (1%)
Asthenia 73 (16%) 9 (2%) 65 (14%) 13 (3%)
Peripheral edema 62 (13%) 3 (1%) 62 (14%) 3 (1%)
Infections and infestations
Upper respiratory tract infection 67 (15%) 4 (1%) 55 (12%) 3 (1%)
Bronchitis 54 (12%) 5 (1%) 25 (6%) 2 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms 70 (15%) 1 (0%) 23 (5%) 3 (1%)
Back pain 64 (14%) 8 (2%) 61 (13%) 10 (2%)
Nervous system disorders
Headache 67 (15%) 4 (1%) 39 (9%) 2 (0%)
Peripheral neuropathies 56 (12%) 7 (2%) 170 (37%) 23 (5%)
Psychiatric disorders
Insomnia 105 (23%) 5 (1%) 116 (25%) 10 (2%)
Respiratory, thoracic, and mediastinal disorders
Dyspnea 128 (28%) 23 (5%) 69 (15%) 8 (2%)
Cough§ 97 (21%) 0 (0%) 61 (13%) 2 (0%)
Vascular disorders
Hypertension** 83 (18%) 30 (7%) 33 (7%) 12 (3%)

Post hoc analysis at median OS: Kd had comparable exposure-adjusted rates of adverse reactions vs Vd3

The rate of adverse reactions was comparable when adjusted for exposure. Given that patients in the Kd arm received 21 more weeks of treatment than those in the Vd arm, the rate of adverse reactions was adjusted for the different treatment durations.

Exposure-adjusted adverse events
Category Kd (n = 463)
r (95% CI)
Vd (n = 456)
r (95% CI)
Any grade AE 1377 (1256-1509) 1755 (1600-1925)
Grade ≥ 3 AE 164 (148-181) 178 (160-199)
Serious AEs 67.9 (60.3-76.5) 65.8 (56.9-76.0)
Grade 5 AE 5.83 (4.12-8.25) 5.98 (3.90-9.17)

Kd resulted in 5x less grade 2 or higher peripheral neuropathy than Vd1

≥ Grade 2 peripheral neuropathy1
Rate of peripheral neuropathy: Kd vs VdRate of peripheral neuropathy: Kd vs Vd

Among patients in the Vd group, 82% received subcutaneous Velcade® (bortezomib) throughout their treatment.1

Kd = KYPROLIS®+dexamethasone; Vd = Velcade® (bortezomib)+dexamethasone; r = exposure-adjusted subject rate per 100 subject years; AE = adverse event; OS = overall survival; CI = confidence interval.

Median treatment duration

The median treatment duration was 48 weeks (12 cycles) with Kd vs 27 weeks (8 cycles) with Vd1,6

Median treatment duration (Kd vs Vd)
The median treatment duration was 48 weeks (12 cycles) with Kd vs 27 weeks (8 cycles) with VdThe median treatment duration was 48 weeks (12 cycles) with Kd vs 27 weeks (8 cycles) with Vd

Select frail-subgroup safety profile (Kd 56 mg/m2 vs Vd)7

SELECT GRADE ≥ 3 TEAEs OF INTEREST
Select grade ≥ 3 TEAEs of interest, n Kd (n = 168) Vd (n = 159)
Peripheral neuropathy 4 15
Acute renal failure 15 7
Cardiac failure 15 7
Ischemic heart disease 8 6
Pulmonary hypertension 0 1
DISCONTINUATION RATES DUE TO TEAEs
REFERENCES

1. KYPROLIS® (carfilzomib) prescribing information, Onyx Pharmaceuticals Inc., an Amgen Inc. subsidiary. 2. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27-38. 3. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:1327-1337. 4. Liu GF, Wang J, Liu K, Snavely DB. Confidence intervals for an exposure adjusted incidence rate difference with applications to clinical trials. Stat Med. 2006;25:1275-1286. 5. Siddiqui O. Statistical methods to analyze adverse events data of randomized clinical trials. J Biopharm Stat. 2009;19:889-899. 6. Data on file, Amgen; 2017. 7. Facon T, Niesvizky R, Weisel K, et al. Carfilzomib in relapsed or refractory multiple myeloma: frailty subgroup analysis from phase 3 ASPIRE and ENDEAVOR. Poster presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA.

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IMPORTANT SAFETY INFORMATION FOR KYPROLIS

Cardiac Toxicities

  • New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of administration.
  • Monitor patients for signs or symptoms of cardiac failure or ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse reactions until recovery, and consider whether to restart at 1 dose level reduction based on a benefit/risk assessment.
  • While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate.
  • For patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment prior to starting treatment with KYPROLIS and remain under close follow-up with fluid management.

Acute Renal Failure

  • Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency (including renal failure) have occurred. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Tumor Lysis Syndrome

  • Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred. Patients with a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, and withhold until resolved.

Pulmonary Toxicity

  • Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.

Pulmonary Hypertension

  • Pulmonary arterial hypertension (PAH) was reported. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart based on a benefit/risk assessment.

Dyspnea

  • Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart based on a benefit/risk assessment.

Hypertension

  • Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart based on a benefit/risk assessment.

Venous Thrombosis

  • Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed. Provide thromboprophylaxis for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
  • For patients using hormonal contraception associated with a risk of thrombosis, consider an alternative method of effective contraception during treatment.

Infusion-Related Reactions

  • Infusion-related reactions, including life-threatening reactions, have occurred. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration. Premedicate with dexamethasone to reduce the incidence and severity of infusion-related reactions.

Hemorrhage

  • Fatal or serious cases of hemorrhage have been reported. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.

Thrombocytopenia

  • KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Monitor platelet counts frequently during treatment. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure

  • Cases of hepatic failure, including fatal cases, have occurred. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.

Thrombotic Microangiopathy

  • Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome, have occurred. Monitor for signs and symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)

  • Cases of PRES have occurred in patients receiving KYPROLIS. If PRES is suspected, discontinue and evaluate with appropriate imaging. The safety of reinitiating KYPROLIS is not known.

Progressive Multifocal Leukoencephalopathy (PML)

  • Cases of PML, including fatal cases, have occurred. In addition to KYPROLIS, other contributary factors may include prior or concurrent use of immunosuppressive therapy. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue and initiate evaluation for PML including neurology consultation.

Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

  • In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse reactions was observed in patients in the KMP arm. KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.

Embryo-fetal Toxicity

  • KYPROLIS can cause fetal harm when administered to a pregnant woman.
  • Advise pregnant women of the potential risk to a fetus. Females of reproductive potential should use effective contraception during treatment with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should use effective contraception during treatment with KYPROLIS and for 3 months following the final dose.

Adverse Reactions

  • The most common adverse reactions in the combination therapy trials: anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia.
  • The most common adverse reactions in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

Please see accompanying full Prescribing Information.

INDICATIONS

  • KYPROLIS® (carfilzomib) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
  • KYPROLIS® is indicated as a single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

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